Growth retardation occurs invariably in children with chronic renal failure; secondary hyperparathyroidism and tissue resistance to the actions of IGF-1 are major contributors to impaired growth. Calcitriol and recombinant human growth hormone are widely utilized to improve liner growth in children, but large intermittent doses of calcitriol have been shown to suppress bone formation and to induce adynamic lesions of bone; moreover, substantial reductions in linear growth have been reported during intermittent calcitriol therapy in children with renal therapy. These findings suggest that calcitriol can modify chondrocyte proliferation and/or differentiation in epiphyseal growth plate cartilage and may counteract the effect of recombinant human growth hormone to increase linear growth in children with chronic renal failure; the mechanisms responsible for these changes remain unknown. Parathyroid hormone related peptide (PTHrP) and the PTH/PTHrP receptor play critical roles in regulating chondrocyte differentiation in the epiphyseal growth plate, and PTH/PTHrP receptor expression is down- regulated in the growth plate cartilage of rats with renal failure; there is limited information, however, about the impact of renal bone disease per se or treatment with calcitriol or growth hormone is modifiers of the expression of PTH/PTHrP or other molecular markers of endochondral bone formation in renal failure. In the current project, chondrocyte proliferation will be assessed by bromodeoxyuridine (BrdU) incorporation and apoptosis of hypertrophic chondrocytes will be measured by the TUNEL assay in rats with renal failure and either secondary hyperparathyroidism or adynamic lesions of bone; the width of the growth plate will also be measured by quantitative histology. The technique of in situ hybridization will be used to quantify the expression of mRNAs for the PTH/PTHrP receptor, type II and type X collagen, alkaline phosphatase and IGF-1 in each disorder. The separate and combined effects of calcitriol and growth hormone on selected molecular markers on endochondral bone development will be examined in rats with adynamic renal bone disease, and the effect of continuous versus intermittent calcitriol therapy on the expression of these markers will be determined. The results of these studies will determine whether alterations in the regulation of chondrocyte proliferation and differentiation contribute to impaired linear growth in experimental renal failure and whether changes in the expression of known regulators of endochondral bone formation and chondrocyte differentiation account for these disturbances in vivo.